title: Glial S100B protein modulates mutant ataxin-1 aggregation and toxicity: TRTK12 peptide, a potential candidate for SCA1 therapy.
abstract: Non-cell autonomous involvement of glial cells in the pathogenesis of polyglutamine diseases is gaining recognition in the ataxia field. We previously demonstrated that Purkinje cells (PCs) in polyglutamine disease spinocerebellar ataxia-1 (SCA1) contain cytoplasmic vacuoles rich in Bergmann glial protein S100B. The vacuolar formation in SCA1 PCs is accompanied with an abnormal morphology of dendritic spines. In addition, S100B messenger RNA (mRNA) expression levels are significantly high in the cerebella of asymptomatic SCA1 transgenic (Tg) mice and increase further with age when compared with the age-matched wild-type animals. This higher S100B mRNA expression positively correlates with an increase in the number of vacuoles. To further characterize the function of S100B in SCA1 pathology, we explored the effects of S100B protein on GFP-ataxin-1 (ATXN1) with expanded polyglutamines [82Q] in HEK stable cell line. Externally added S100B protein to these cells induced S100B-positive vacuoles similar to those seen in SCA1 PCs in vivo. Further, we found that both externally added and internally expressed S100B significantly reduced GFP-ATXN1[82Q] inclusion body formation. In contrast, the addition of S100B inhibitory peptide TRTK12 reversed S100B-mediated effects. Interestingly, in SCA1 Tg mice, PCs containing S100B vacuoles also showed the lack of nuclear inclusions, whereas PCs without vacuoles contained nuclear inclusions. Additionally, TRTK12 treatment reduced abnormal dendritic growth and morphology of PCs in cerebellar slice cultures prepared from SCA1 Tg mice. Moreover, intranasal administration of TRTK12 to SCA1 Tg mice reduced cerebellar S100B levels in the particulate fractions, and these mice displayed a significant improvement in their performance deficit on the Rotarod test. Taken together, our results suggest that glial S100B may augment degenerative changes in SCA1 PCs by modulating mutant ataxin-1 toxicity/solubility through an unknown signaling pathway.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. pvig@umc.edu
authors.forename: Parminder J S
authors.initials: PJ
authors.lastname: Vig
authors.forename: Scoty
authors.initials: S
authors.lastname: Hearst
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Shao
authors.forename: Mariper E
authors.initials: ME
authors.lastname: Lopez
authors.forename: Henry A
authors.initials: HA
authors.lastname: Murphy
authors.forename: Eshan
authors.initials: E
authors.lastname: Safaya
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D015153:Blotting, Western; D051347:CapZ Actin Capping Protein; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000378:metabolism* / Q000473:pathology; D014617:Vacuoles / Q000378:metabolism / Q000473:pathology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D051347:CapZ Actin Capping Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; C475482:TRTK-12 peptide